1. Field of the Invention
The present invention relates to a new class of dinuclear platinum complexes. It also relates to a process for their preparation. The invention further relates to the pharmaceutical compositions containing them and to their use for the therapeutic treatment of various cancers.
2. Description of the Background
Cisplatin and oxaliplatin are known cytostatic antineoplastic agents, which are advantageously used in the therapeutic treatment of various cancers.
Cisplatin is prescribed in particular for treating cancers of the testicles, of the ovaries, epidermoid cancers, for treating tumors of the head, of the neck, etc.
Oxaliplatin is prescribed for treating the same type of cancers, more particularly cancers of the ovaries, as well as cancers of the colon, of the upper respiratory tracts and epidermoid cancers.
Each one of these antineoplastic agents has its own specificity and, as a result, as a function of the stage of evolution of the disease, of the patient's condition or of the type of cancer to be treated, the practitioner may be led to prescribe either one of said agents. In certain cases however, the sought therapeutic effect is not reached or at least its maximum level is not reached.
Like other cytostatic antineoplastic agents, in particular other organometallic derivatives of platinum, cisplatin and oxaliplatin have an intrinsic toxicity which constitutes a serious limiting factor which the practitioner has to take into account in the prescribed treatment. In particular, cisplatin has a rather significant renal and neuromotive toxicity, all the more so as said toxicity has proved to be cumulative. It also provokes strong vomiting and can cause bradycardia, as well as myelosuppression. To a lesser degree, oxaliplatin causes a reversible sensorial dysesthesia, the effects of which can be easily reduced by suitably modulating the dose administered to the patient. But the result is that the practitioner is therapeutically limited particularly as far as curing means are concerned.
Oxaliplatin belongs to the class of platinum(II)-trans-1,2-diaminocyclohexane complexes which are currently in full development. Said complexes, or "dach" complexes are being clinically tested in Europe, and in particular in France, as well as in the United States and Japan and they are especially efficient against melanomae and tumors of the ovaries, of the uterus, of the stomach and of the intestine, etc.
U.S. Pat. No. 4,169,846 describes such complexes, namely cisplatin(II) complexes and complexes of 1,2-diaminocyclohexane, in particular the [Pt(II)-oxalato (1R),(2R)-diaminocyclohexane] complex which is the compound known under the designation of oxaliplatin.
When said "dach" complexes are combined with 5-fluorouracile (5FU), they are particularly efficient for treating cancers of the stomach.
And when they are combined with the 5-fluorouracile and folinic acid, the "dach" complexes are especially useful for treating cancers of the colon.
Patent EP-A-143 478 relates to a method of administration of cisplatin in the form of an acid aqueous solution, and more specifically an hydrochloric acid solution having a pH preferably comprised between 3.2 and 3.5 and containing chloride ions for example from sodium chloride for stabilizing the solution and thus avoiding hydrolysis.
U.S. Pat. No. 4,177,263 which also relates to cisplatin, describes a method for treating cancer tumors in animals, which method consists in injecting by parenteral route a complex platinum agent in an efficient quantity for causing regression of the tumor.
Clinical tests conducted in France on the use of the combination of oxaliplatin with cisplatin have shown the remarkable effect of such combination on the cancer of the liver. However, it has been found that there are problems of stability with the combined complexes.
International patent application WO 94/12193 describes in particular a composition intended for the joint administration of cisplatin and oxaliplatin as a combination after extemporaneous reconstitution by addition of aqueous liquid in the form of a lyophilisate containing the cisplatin and the oxaliplatin in a weight ratio comprised between 2:1 and 1:2.